In the previous period of funding by the PSW RCE, we have studied the entry pathways used by the New World clade B arenaviruses. This sub-group of the Arenavirus family contains 5 emerging human pathogens, capable of causing severe hemorrhagic fevers. Since clade B contains both pathogenic and non-pathogenic members, it has proved to be a powerful system with which to elucidate the determinants of human pathogenicity. We have identified several key differences between the two groups, including the fact that human transferrin receptor 1 (TfR1) is only used as a cellular receptor by the human pathogens. This suggests that the virus glycoprotein (GP)-TfR1 interaction is likely of great importance for the ability of clade B arenaviruses to infect humans. This finding has several implications: (1) it is likely that the interaction between GP and TfR1 will represent a good therapeutic target, (2) the ability of any newly discovered clade B arenaviruses to use TfR1 may be a good predictor of human pathogenic potential, and (3) targeting antiviral drugs to cells that express TfR1 may promote the delivery of therapeutics to the same cells that the viruses preferentially infect. TfR1 is not the only cellular receptor to be used by the arenaviruses. Previously, a-dystroglycan was shown to play an important role in the entry pathway of several arenaviruses, including Old World and New World clade C viruses, and our own data indicates that at least 2 other unknown receptors are used by this family. Such receptor choice flexibility within the arenaviruses suggests that these viruses could continue to evolve in directions that would allow other species-jumping events into humans. Our goals for the next 5 years of funding are to continue to build a more complete picture of receptor use by the New World arenaviruses, and to exploit this information in the development of anti-arenaviral therapeutics, including TfR1-targeted siRNA nanoparticles. Simultaneously, we will develop better BSL-2 animal models with which to evaluate the effectiveness of these reagents.